PROJECT SUMMARY Over the past several decades, the prevalence of gestational diabetes (GDM) has increased 3-fold, with implications for the growing type 2 diabetes (T2DM) epidemic among women with a history of this condition. An increasing body of literature suggests that phthalates, an endocrine disrupting chemical, are associated with increased T2DM risk in non-pregnant women. These chemicals are used in plastics, food packaging, cosmetics, and other consumer products. Phthalates bind to the nuclear receptors, peroxisome proliferator activated receptors (PPAR) alpha and gamma, which may modulate target genes that regulate glucose metabolism. While phthalates have been found to be associated with T2DM risk among non-pregnant women, it remains unclear whether these chemicals are associated with GDM risk. Preliminary data from our research suggest associations between urinary levels of mono-benzyl (MBzP) and mono-(3-carboxypropyl) (MCPP) phthalates and pregnancy-related risk factors of GDM, such as increased pre-pregnancy weight, excessive gestational weight gain, and elevated blood glucose levels during pregnancy among a subset of women (n=350) participating in an ongoing pregnancy cohort study of 4,000 women. Yet, no studies have assessed the association between phthalate levels and GDM risk. In addition, GDM is known to substantially increase future development of T2DM, with over 50% of women with a history of GDM going on to develop T2DM. This increased risk can be seen as early as 6-weeks postpartum, with women with higher fasting and 2-hour blood glucose levels being at substantially higher risk of developing T2DM in the future. However, no studies have evaluated the association between phthalate levels during and after pregnancy to determine whether these chemicals contribute to an increased risk of sustained glucose dysregulation after pregnancy. To this end, we propose conducting a nested case-control study in an established pregnancy cohort to assess the association between 1st and 2nd trimester urinary metabolite levels of mono-benzyl phthalate and mono-(3-carboxypropyl) phthalate and GDM risk, as well as biomarkers associated with GDM risk (i.e. blood glucose levels) among 560 women. We will also conduct a post-pregnancy follow-up study in 866 newly recruited women, including those with GDM, impaired glucose tolerance, and normal glycemia, to evaluate the association of higher pregnancy and post-pregnancy levels of MBzP and MCPP and post-pregnancy glucose, insulin, hemoglobin A1c, and HOMA-IR levels at 6-weeks postpartum as measures of sustained glucose dysregulation after pregnancy. By evaluating the role of phthalate levels and diabetes risk at two sensitive time points?pregnancy and the postpartum, this research will give better understanding for the role of these highly-prevalent endocrine disrupting chemicals on GDM and future T2DM risk, with implications for identifying modifiable risk factors.